8,9-epoxyperillartine sweeteners

ABSTRACT

8,9-Epoxyperillartine optical isomers having good sweetness and no or moderately low bitter aftertaste characteristics, along with an increased solubility in water as compared with the corresponding perillartine precursor isomers. These epoxy derivatives are also free of the undesirable gingery-licorice taste of perillartine. The new compounds give no evidence of toxicity and can be employed in foods as synthetic sweetening ingredients.

United States Patent Acton et al.

[151 3,699,132 1 Oct. 17, 1972 [54] 8,9-EPOXYPERILLARTINE SWEETENERS[72] Inventors: Edward M. Acton, Menlo Park;

Morris A. Leaffer, Palo Alto; Her- [21] Appl. No.: 69,165

[52] US. Cl. ..260/348 R, 99/141 A [51] Int. Cl. ..C07d l/00, C07d H06[58] Field of Search... ..260/348 [56] References Cited OTHERPUBLICATIONS E. Klein et al., Tetrahedron, Vol. 19, pp. 1,091- 1,099(1963).

Primary Examiner-Norma S. Milestone Attorney-Donovan J. De Witt andGregg, Hendricson & Caplan [57] ABSTRACT 8,9-Epoxyperillartine opticalisomers having good sweetness and no or moderately low bitter aftertastecharacteristics, along with an increased solubility in water as comparedwith the corresponding perilla'rtine precursor isomers. These epoxyderivatives are also free of the undesirable gingery-licorice taste ofperillartine. The new compounds give no evidence of toxicity and can beemployed in foods as synthetic swee nin in 4 Claims, No Drawings 8,9-EPOXYPERILLARTINE SWEETENERS BACKGROUND OF THE INVENTION The variousenantiomeric or optical isomers of perillartine, as well as racemicmixtures (1) thereof, are known to have utility as synthetic sweeteningagents, the perillartine, for example, being called perilla sugar andused as a sweetening agent in Japan. These isomers are the startingmaterials employed in forming the compounds of this invention,'andmethods for their preparation are described in French Pat. No-1,813,849, to Kergomard et al., dated July 15, 1959. Also, .a synthesisof perillartine is reported by Ando et al., Science (Tokyo) 17, 2411947), C. A. 45, 1976 d.(l95l), and methods for isolating this isomerfrom plant sources are also described in Beilstein, 7, 2nd Suppl, page130, and in the 3rd Suppl. at page 566. Racemic perillartine ismanufactured and sold by Yuki Gosei Kogyo Company in Japan.

Perillartine is commonly described in the literature as beingapproximately 2,000 times, sweeter than sucrose. However, this sweettaste is accompanied not only by the somewhat bitter aftertaste which ispresent to a greater or lesser degree with all synthetic sweeteners, butalso by a pronounced 1icorice-like,'or gingery-licorice flavor which hasruled out any usage of the product in this country. Perillartine (alloptical isomers) has a maximum water solubility, at 25 C., of about0.0003 M. This concentration is sufficient to provide a pleasantly sweetaqueous solution.

I SUMMARY OF THE INVENTION In accordance with the invention, there areprovided novel or (i) 8,9-epoxyperillartine optical isomers having theformula 8 9 CH3- ---CH1 The new compounds are white crystalline solids.

The numbering system used in the foregoing formula is that employed inconnection with terpenes such as menthene. By another system ofnomenclature, the optical isomers corresponding to the above formula canbe designated as 4-(1,2-epoxy-2-propyl)-l-cyclohexene-l-carboxaldehyde,syn-oximes. However, the terpene system of nomenclature indicated in theformula will be employed herein to designate the isomer compounds ofthis invention.

The optical isomer compounds of this invention, which include the or (d)isomer, theor (1) isomer and the racemic (i), or (d l isomer mixture aredesignated as 8,9- epoxyperillartines. In this connection, it may benoted that perillartine has the same formula as that shown above exceptthat no epoxy group is present, and the number 8 and number 9 carbonatoms are joined by an olefinic double bond.

The 8,9-epoxyperillartine compounds hereof are white crystallinematerials having a sweetness ranging variously from about 20 to 50 timesthat of sucrose, and

a solubility in water at 25 C. of about 0.003 M, or roughly 10 timesthat of perillartine. They are highly soluble in ethanol, benzene,acetone and other organic solvents. Further, said compounds have bitteraftertaste characteristics ranging from none to moderate and, quiteunexpectedly, they are free of the undesirable gingery-licorice tastewhich characterizes the corresponding perillartine optical isomers.Aqueous solutions of the 8,9-epoxyperillartine, at concentrations ofapproximately 0.003 M, are pleasantly sweet and highly palatable. In thedry state the present compounds have an excellent shelf life, andaqueous solutions thereof are stable under weakly basic conditions. Theygive no evidence of toxicity and are well adapted to be used, in the drypellet or powder form, as synthetic sweetening agents either aloneor inconjunction with other sweetening agents such assucrose, dextrose,saccharine or the various cyclamates. They are also well adapted to beadmixed, in dry form, with other food ingredients such as citric acid,flavoring, spices, starches, preservatives, dehydrated food stuffs andthe like. I I

The 8,9-epoxyperillartines of this invention can be prepared by theoxidation of the corresponding perillartine optical isomer, or isomermixture, with mchloroperbenzoic acid. The reaction is carried out bydissolving the perillartine in an organic solvent such as benzene, andthen slowly adding m-chloroperbenzoic acid, or a solution thereof insaid solvent. A 10-30 percent molar excess of the peracid is normallyemployed. The ensuing reaction, which is somewhat exothermic, proceedsreadily at room or moderately elevated temperatures. Stirring iscontinued after all the peracid has been added while m-chlorobenzoicacid precipitates out. The system is then filtered, and the filtrate iswashed with sodium bicarbonate solution to destroy excess peracid,followed by washing with water.

After being filtered and dried with a suitable solid desicant, thedesired 8,9-epoxyperillartine isomer present in the solution can berecoveredin good yield by crystallizing the same from solution or bystripping off the solvent in vacuo. The product canbe purified byconventional methods such as recrystallization from appropriate organicsolvents such as hexane, benzene or absolute ethanol.

During the reaction between the perillartine starting material and theperacid oxidant, it has been found that neither the 1,2-double bond inthe ring nor the oxime functional group is affected. Further, the attackof the 8,9-double bond is highly stereoselective in that but one of thetwo possible stereomeric forms of the epoxide is produced.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The following examplesillustrate the invention but are not to be construed as limiting thesame.

EXAMPLE 1 To a stirred solution of 2g (0.0121 mole) of racemicperillartine in ml. benzene at 25 C. is added, in portions over a 10minute period, 3.2 g (0.0158 mole) of percent m-chloroperbenzoic acid (apowdered dry solid) during which period the temperature rises to 30 C.The resulting solution is stirred for 12 hrs. while mchlorobenzoic acidis precipitated. The system is filtered and the filtrate is washed firstwith two 50 ml. portions of saturated aqueous sodium bicarbonate, andthen with 50 ml. of water. After being dried with magnesium sulfate, theremaining liquid is concentrated in vacuo, at 25 C., until crystalsstart to form. These crystals are then dissolved with heating, followingwhich the solution is cooled to induce crystallization of the8,9-epoxy-perillartine product. On being recrystallized from benzene,the product is recovered as a white solid, mp. 125l 26 C., which isslightly soluble (0.003 M) in water at 25 C. and has good solubility inhexane, benzene, alcohol and other. organic solvents. This material isfound to be homogeneous by thin-layer chromatography in chloroform-ethylacetate (1:1) on silica gel, it having R, 0.52 compared to the (i)perillartine starting material having R, 0.62. (These properties are thesame whether racemic or enantiomeric perillartineis employed as thestarting material). The product isidentified as (t) 8,9-epoxyperillartine by infrared and nuclear magnetic'resonance spectra.This is confirmed by elemental analysis which shows the compound to havecarbon, hydrogen and nitrogen contents of 66.47, 8.49 and 7.75percent,,respectively, as against theoretical values for these elementsof 66.27, 8.34 and 7.73 percent, respectively.

EXAMPLE 2 The foregoing Example 1 is repeated under essentially the sameconditions except that perillartine rather than (i) perillartine isreacted with the mchloroperbenzoic acid. Here the 8,9-epoxyperillartineobtained as product is also identified by infrared and nuclear magneticresonance methods of analysis. Elemental analysis shows it to havecarbon, hydrogen and nitrogen contents of 66.08, 8.31 and 7.67 percent,respectively, as compared with theoretical values for these elements of66.27, 8.34 and 7.73 percent, respectively. This compound has a meltingpoint of 116 117 C. and an optical activity [01],, 24 of -l05.6 at 1percent concentration in ethanol. Its solubility characteristics are thesame as those for the racemic isomer mixture of Example 1.

EXAMPLE 3 Again following the procedure of Example 1, but substitutingperillartine for the (:t) perillartine starting material, there isobtained 8,9-epoxyperillartine as a white solid having a molecularweight of 165.24. This compound has somewhat reduced sweetness and ahigher bitter aftertaste than either the racemic isomer mixture or theisomer of the foregoing examples. Its solubility characteristics are thesame, however, as those of the other isomer materials. This compound, itwill be noted, forms approximately one-half of the isomer mixture ofExample 1.

EXAMPLE 4 Taste tests by a panel consisting of 6 subjects are conducted,to evaluate the relative sweetness characteristics of the (i) and the8,9-epoxyperillartine of Example 1 and 2, respectively. In these testseach subject matches the sweetness of a given aqueous'solutioncentration. It is found that the racemic (:t) isomer mixture at a levelin water of 0.054 percent (0.003 M) tastes relatively sweet and is'equalin this respect to a 3.1 percent (0.09 M) aqueous solution of sucrose,its relative sweetness thus being at least 30 times that of thereference sucrose material.

Similarly, the 8,9-epoxyperillartine at the same concentration (0.003 M)is found to be equal in sweetness to a 4.1 percent (0. 12 M) sucrosevsolution on this direct comparison basis. lts relative sweetness is thusabout 40 or more times that of sucrose. Further, the 0.003 M solution ofthis isomer, while pleasantly sweet, is moderately sweeter thanthe 0.003M solution of the (i) isomer.

EXAMPLE 5 and 2 hereof. In this test, each compound, in aqueoussolution, is tasted a total of 12 to 36 times by the members of thepanel. The data obtained by the panel show that, out of a total tastescore of percent, the racemic 8,9-epoxyperillartine isomer mixture ofExample 1', at concentrations of both 0.002 M and 0.003 M, has asweetness of 70 to 72 percent and a bitterness of 15 percent. Thebalance (13 to 15 percent) is attributable toother taste qualities, noneof which is objectionable to the palate. In particular, there is nocharacteristic perillartine flavor.

In tests with the 8,9-epoxyperillartine isomer of Example 2, thesolutions of both 0.002 M and 0.003 M show a sweetness of 92m 94percent, no bitterness, and 6 to 8 percent of other tastequalities of anunobjectionable, non-perillartine character.

EXAMPLE 6 ic. This is determined in experiments wherein the racemicisomer mixture, as prepared in Example 1, is injected I. V. into ratsweighing 200 g at rates as high as 300 mg. per kg of body weight, over24 hours.

Similarly, this same compound is injected I.P. into rats and into mice(18 20 g) at rates as high as 30 mg per. kg of body weight, over 24hours. In making these injections, the chemical is dissolved in a 5percent solution of propylene glycol in water. From this work theconclusion is drawn that this sweetener compound does not cause deathand does not give any evidence whatsoever of toxicity.

We claim:

1.An enantiomeric isomer of 8,9-epoxyperillartine or mixtures thereof.

2. An enantiomeric isomer according to claim 1 which is8,9-epoxyperillartine.

3. An enantiomeric isomer according to claim lv

2. An enantiomeric isomer according to claim 1 which is (-)8,9-epoxyperillartine.
 3. An enantiomeric isomer according to claim 1which is (+) 8,9-epoxyperillartine.
 4. A racemic or other mixture of (-)8,9-epoxy-perillartine and (+ ) 8,9-epoxyperillartine, according toclaim 1.